Our own contribution was a review on the interactions of heparan sulfate with proteins and one on polysaccharide sulfotransferases. It has been 16 years since we wrote a review on the first topic and since there have been substantial advances. We took the opportunity to build up from the basics to some new(ish) ideas on the selectivity of these interactions and how they may control the diffusion of heparan sulfate-binding proteins in the extracellular space. Polysaccharide sulfotransferases are pretty much terra incognita. They occur across the Tree of Life, yet the majority of our data are on the mammalian Golgi enzymes; putative enzymes are the overwhelming majority in this field!

In the summer I started my engagement with Dulce Papy-Garcia’s department in UPEC; my relationship to the department goes back to the mid 1990s and I have always found it to be a most stimulating environment. It transpired that her Group had undertaken a massive analysis of the enzymes involved in heparan sulfate biosynthesis and from that had elaborated an exciting new hypothesis regarding its regulation, which amongst other things explained the counter intuitive phenotypes of a number of genetic disorders. I emailed Jon Mueller to ask if there was still space in the sulfation issue of Essays in Biochemistry – there was, so with Dulce we set about knocking their analysis into the shape of a review. The result was the third review which provides a new model to explain the phenotypes that result from genetic variation in the genes encoding the enzymes and transporters involved in heparan sulfate proteoglycan biosynthesis.

Reviews at Essays in Biochemistry are subjected to peer review, and for all three of these reviews the comments were both incisive and useful, allowing us to improve the articles. So a thank you to the reviewers for taking the time to read our submissions and provide us with the benefit of your ideas and insights. Another great plus is that Portland Press’ electronic proofing system is a pleasure.

Reviews do take a substantial effort, so now it is time to return to those drafts of primary research papers and finish them!

This we thought would be a simple matter. 

It turned out to be one of the most difficult papers Ed and myself have written, to the extent that after N drafts (where N is a significantly larger number than either of us had experienced in any previous writing exercise) and too many summers we still had nothing satisfactory. So, we cunningly inveigled two colleagues, Tim Rudd from NIBSC and Marcelo Lima from Keele to join us on what we advertised as the sunny beach of sulfate and phosphate, but which in reality was a rather dank quagmire. There is though something about strength in numbers, and with very helpful input from Steve Butler in Loughborough, we arrived at what we considered a satisfactory synthesis. Happily, the reviewers concurred, and the paper is now published at Royal Society Interfaces, “Phosphorylation and sulfation share a common biosynthetic pathway, but extend biochemical and evolutionary diversity of biological macromolecules in distinct ways”.

This is by no means the last word on the matter, but along with some previous thoughtful papers we cite (if we have missed one, please let me know) it provides some ideas that may help us to understand why biology co-opted particular elements from the inorganic world to perform groups of functions vital to life as we know it now.

Earlier this year Simon Wheeler (who now has a well deserved substantive position, congratulations!) and Steve Butler published the first output from the BBSRC TDRI awarded to Steve, with myself and Ed Yates in supporting roles. It is always nice to collaborate with real chemists, as it reminds me I am very much a pseudo chemist, and I learn a lot. After what I would consider a quite heroic effort on the synthesis front, Simon and Steve pulled out a very useful sensor, based on a europium complex. The Eu sensor has good selectivity for PAP over PAPS, the universal sulfate donor. The assay works well and is very amenable to high throughput 384 well format assays (= more papers on the way). So we can now measure sulfotransferase activity in realt-ime independently of the acceptor for pretty much any enzyme-substrate combination. This represents an important tool for the wider sulfotransferase community. 

The paper also demonstrates the importance of social media in science, as a means to access in a non-direct manner new information that sets off an innovative project. I saw tweet from @Fieldlab highlighting a paper from Steve’s lab on lanthanide sensors able to discriminate nucleotide phosphates and read the paper. Naively I thought PAP/PAPS sensing using such compounds should be easy, so I contacted Steve. After some preliminary tests with PAP and PAPS on his side, we wrote the grant – another lesson here, as the application neared final from I went over to Loughborough for a meeting, which allowed us to iron out a few problems far more effectively than by electronic communication. The work was, as hinted above, far from straightforward, but like everything that is new, very rewarding and continues to be so.

I have just moved from the bird site to the proboscidean one and things look like there will be even more of such ‘random access’ of information there, so let’s see what turns up!

The bottom line here is that anyone making the statement ‘coming out of the Covid environment’ has not kept up with the data, which demonstrate the following:

1. Transmission is ~ 98% via airborne aerosols, known since March 2020 and firmly established by initial rules on masking and regions where this is maintained.

2. The pandemic is unabated. Cases remain high, with several waves a year. This to the extent that hospital beds fill up every wave, world-wide health care workers are burning out due to overwork and waiting lists are getting so long that the best option is becoming the avoidance of ill health.

3. Deaths are lower due to vaccines, but SARS-CoV-2 is an adept immune escapologist

4. Long Covid is a growing socio-economic problem, a consequence is the loss of members of an organisation’s workforce.

5. Viral persistence is measurable 15 months after recovery, and among the targets is bone marrow and the immune system.

6. There is no cure and no efficacious treatment, and this is true  for acute infection (when you have overt symptoms for ~ 10 days), viral persistence (months/years, see below) and LongCovid (see below). This is in contrast to HIV.

The consequences of the above are that organisations need to:

A. Explicitly state that masks are expected to preserve the health of yourself and of your co-workers and provide masks to the workforce.

B. Explicitly provide details on ventilation of rooms occupied by the workforce and/or install HEPA filters in all such rooms.

C. Expect those with even partial symptoms have a clear LFTs before returning to work.

D. Provide updates on the status of current variants, how much we don’t know and the extent to which Public Health surveillance is reliable.

Anything else is a gross dereliction of duty on the part of an organisation’s management.

Below I take each of the above statements and provide the evidence, including links. If any reader from my workplace, the University of Liverpool can come up with an argument based on evidence why we should not take all possible measures against transmission, then I will accept that the University does not need to take such measures. Until then, not doing so remains a gross dereliction of duty.

Transmission

Transmission is ~98% by airborne aerosols. Aerosols DO NOT drop to the ground, they remain airborne, and the only protection is to reduce their concentration. This is achieved by two complementary routes:

Masks to reduce the amount of aerosols put into the air by an infected person;

Ventilation and filtration to ensure rapid dilution.

Some resources and comments on these

A nice article in PNAS on how secondary physical measures work, which should be on the desk of every organisations’ Health and Safety Office.

A very simple message from JAMA in an article on this subject

“Because no single approach is 100% effective in preventing COVID-19, prevention measures work best when layered, including vaccination and nonpharmacologic interventions that reduce inhalation of infectious particles.”

The same article makes further excellent points. One on the long-term implications for building design

“Reducing contaminants in shared air by improving air handling systems in buildings is an attractive, broadly effective structural measure that does not require repeated individual actions.”

There is a nice Sci-Comm piece here.

The evidence on the efficacy of the different layers of is that you are safer in a small room with an unvaccinated person, both wearing a FFP2/N95 masks, than in the same room, both vaccinated but  without masks.

We should of course as far as possible have all measures in place.

Pandemic is unabated

Data acquisition is being dismantled, so it is essential to employ critical faculties. The testing programme is no longer functional, since you cannot report the results of tests purchased privately. Moreover, the excellent ONS survey will soon be limited, so we will have even less information on the number infected later in the year, and the only proxy will then be NHS data on admissions and bed occupancy.

For the record the ONS survey data are here and for the week ending 29 June 2022 for England the estimated number of people testing positive for COVID-19 was 2,154,000 (95% credible interval: 2,062,600 to 2,247,100), equating to 3.95% of the population, or around 1 in 25 people.

There are very useful analyses of these data, which I recommend, e.g., @TravellingTabby on Twitter who maintains an excellent data web page from the ONS data

The idea that the virus is attenuating is WRONG. As usually small numbers, large effect sizes, when we go to a good sized study (130 k patients) there is no evidence that Omicron is milder

Deaths are lower

The estimate from WHO is that vaccines have avoided 20 M deaths. However, excess deaths over historical average still substantial. The problem is that the efficacy of the vaccines is good, but not nearly good enough. This is compounded by giving the virus a free reign so that natural selection can operate at extremely high throughput. The result is a virus that was already good at immune escape is now a master. Some data in the links below.

The Tweetorial from Deepti Gurdasani covers a recent Science paper that demonstrates immune escape and that T-cell immunity to Omicron is poor at best

The paper is here.

Long Covid

This occurs in a significant number of people after they recover from acute infection. The risk only reduced a little by vaccination according to this large study of 33 k people infected after vaccination with over 13 M controls!

A key take home message from this paper is:

“Altogether, the findings suggest that vaccination before infection confers only partial protection in the post-acute phase of the disease; hence, reliance on it as a sole mitigation strategy may not optimally reduce long-term health consequences of SARS-CoV-2 infection. The findings emphasize the need for continued optimization of strategies for primary prevention of BTI and will guide development of post-acute care pathways for people with BTI. 

Importantly, the risk of LongCovid increases with each infection.

The ONS (UK) data form early April 2022 indicate 1.7 million people with LongCovid in the UK (2.7% of the population), and it also affects the young…:

“40,000 aged 2-11 (confidence intervals 32K-48K) 59,000 aged 12-16 (confidence intervals 52K-66K) That’s a total of 99,000 children “

For those aged 17-24, that’s 89,000 (CI 77K-102K)

For those with an illness duration of at least A YEAR: 14,000 aged 2-11 (confidence intervals 9K-19K) 17,000 aged 12-16 (confidence intervals 13K-20K) That’s a total of 31,000 children. For those aged 17-24, that’s 45,000 (CI 36K-54K).

Unfortunately, those affected cannot pursue their usual lives and work, studies, hobbies, etc., are largely or completely suspended.

There is good evidence that micro clots are part of the problem and it seems likely that viral persistence in our organs may also contribute.

Viral persistence

Data from autopsies demonstrate viral persistence in organs in even moderate cases (so no hospitalisation) up to 15 months post infection. These data are likely to get worse, rather than better as we progress into the pandemic and we acquire more time-dependent data.

There is no cure and vaccines are an aid, but not a solution

The drugs we have are merely re-purposing existing ones, and their efficacy is modest, at best. It will be some time, 5 to 10 years  perhaps, before we have drugs that specifically target SARS-CoV-2 functions such as its polyprotein protease. There is good evidence for microclots playing a role in LongCovid, but we haven’t yet got a clinical trial running with preregistered outcomes etc. – so far we have case reports only.

Current vaccines are losing efficacy against variants more adept at immune escape, an entirely predictable outcome given near zero measures to reduce transmission, so the virus has had an evolutionary field day exploring host-pathogen interactions, to our detriment of course.

The future without measures beyond vaccination

Attrition of the workforce, most pronounced in those exposed to large numbers of humans in small spaces, such as healthcare and education.

Attrition of the student population able to undertake studies.

The outcome is that society is not sustainable, in the same way that Medieval societies were not sustainable in the face of population loss due to the Plague. One only has to consider the complex chain of skills that underpin basic everyday aspects of life:

The mobile phone, needs cutting edge sills in materials, chips, telecommunications networks, GPS satellites, electricity production, and of course software in all elements of the chain. 

Take out 10% of the workforce and we struggle. Currently over 2.7 % of the population are affected, ~0.9 % to the extent they cannot work, and this after just 2.5 years of the pandemic. What can we withstand? 5%, 10 %? I don’t know, but I cannot see a valid argument for testing the hypothesis that society can withstand X% of LongCovid. If you have one, let me know.

The Future 

Future A We continue to ignore the evidence, and see whether our society can withstand the impact of a large % of its population with LongCovid requiring care and being unable to work. This is a course of action taken by an ideologue, and is not possible for a scientist to act in this way, since in science we critically evaluate evidence.

Future B We apply mitigation measures so as to reduce the frequency of transmission, reduce infections and so the number with LongCovid, until such time as the pandemic is over and/or we have drugs that really work. This is the course of action of any organisation that has the well being of its staff (and students) as a core value, it is evidence- and knowledge-driven, and aims to be sustainable, that is to exist in a recognisable form in 10-50 years time.

“I write this email because University management has abdicated all responsibility towards the wellbeing of their staff and students, and their families. Current University and UK government Covid ‘rules’ contradict the most simple evidence, which is based on exceptionally solid physics and biology/medicine. We are scientists capable of critical thinking, and we should carry these qualities into our daily lives.  

Over the last few weeks our masking at work has become quite poor.

The masks we wear protect others – to protect yourself you need a FFP2 or N95.

Everyone in my group WILL wear a mask at all times except when they are eating. I established this rules before the 2020 lockdown and it has served us well, preventing a number of community acquired cases from spreading to other lab members.

That means wearing a mask properly, over the nose AND mouth.

Why this reminder?

Because

1. The pandemic remains is stronger than in the Spring of 2020, as variants are more transmissible.

2. Vaccines are imperfect, a number of us have children at school who may not be vaccinated (pediatric vaccination is now available and I would recommend it, for reasons explained below)/

3. There is a level of discomfort associated with wearing a mask and often after vaccination.

4. So why? Because Covid is a multi organ systemic disease. You do not have to have severe lung disease to have hits on other organs. ALL major organs are affect4d, brain, heart, liver, kidney, pancreas.

5. The consequence of multi organ systemic disease is long0-term disability. You are all young, you don’t want to spend decades with a major disability or two if you can avoid thi this.

6. Vaccinated people get covid.

7. Vaccinated people who have been infected get re-infected.]

8. Each time you get covid you have a 10% chance of developing Long Covid, that is the multi organ long-term disease that follows infection. This is true for me as it is for children. A simple calculation, take a family of 4, getting infected 2x a year, how long before one of them has Long Covid?

So masks on and properly, as we did in March 2020 before lockdown. Anyone not complying will be sent home.

Dave

Take a look at secondary schools. There are multiple systems. These include:

1.  Comprehensives, select on distance from home.

2. Grammar – select on an exam taken at the start of the last year of primary school

3. Faith – select on religion of parents.

On top of this are academies. These use the exam of Grammar schools, and then inject a lottery element, so applicants are banded and a % of intake comes from each band. Some inject a geographical element too, which is sometimes at first sight counterintuitive: 50% of intake form a particular distance, 50% from more than that distance. It is possible to be one of 1-3 AND an academy.

A decade or so ago I spent some months with a mate gathering information to understand the system and its subtleties.

What I learned was.

1. Faith schools reduce choice. Those with a faith may argue against, but there is plenty of time outside school to pursue their faith and each faith school restricts choice for the majority, simply because only a minority are of one particular faith.

2. Comprehensives that select on distance suffer a major ‘neighbourhood problem’. That is students that were together in primary stay together. This is not good simply from the perspective of child development. There are times in life when you need a clean start and it hampers the secondary school in its efforts to instil a new culture, appropriate for the new level of education.

3. Once I understood the idea behind academies I realised that these were a step forwards. The feedback from heads that converted from comprehensive (or in some cases faith schools with large local catchment) to Academy was that the greater mixing enabled the generation of a new culture in year 7, which had a knock on positive effect on student performance.

3. The perceived success of grammar schools is due to selection. This is not because the students are inherently more able, since an exam assessment in year 6 primary has no predictive value on ability as an adolescent or adult. It is simply due to the fact that it selects for advantaged families. These advantages include ones that are intellectual, e.g., a family that reads a lot, economic, e.g., a family that pays for tutoring, and social, e.g., a family where parent(s) enforce performance. Selection in grammar schools delivers a student body in year 7 that like the academies is not geographically rooted and which is driven, either by the student (not a bad thing) or the parents (likely a bad thing).

Choice is limited, because wherever you live there are many unsuitable schools (faith, wrong faith, geographical selection and so on). If you live in the right part of town, which ironically is often not the leafy suburbs, then choice can be reasonable, but this is not universally true. 

There are many simple improvements to be made, not the least of which is simply to convert all secondary schools to academies, with zero faith element. This promotes mixing

However, this fails to solve a central issue in British education, which I learned from reading a document written by my father. The distinction primary/secondary is merely historical. That is, it evolved with the growth of universal education. It has no basis in human development and biology, as it mixes prepuberty with puberty and post puberty. So running primary runs up to around year 5, middle school to year 9 or 10, secondary to year 13 and tertiary reserved for adults of all ages would be a more efficacious system. This is what is found in many European countries. As someone who teaches in a University, I have found that students from educational systems with a middle school produce far better (in the sense of proactive learners) students than the UK system, though this is a personal view based on experience rather than a large-scale serious study.

A brief recap

Our first foray into the interactions of SARS-CoV-2 with heparin, and so with cellular heparan sulfate (HS), was published just over 2 years ago in March 2020, written up on a GoogleDoc on the  Friday night and the following Saturday. This was not a blind stab, but based on previous work by our Italian colleagues which demonstrated an interaction SARS-CoV with heparin and informed by comparison the receptor binding domain (RBD) of the viruses. In the next months we firmed up the data, put two more preprints out and then at the end of the year the data were eventually published in a peer reviewed journal.

We had considered that the SARS-CoV-2 spike protein might use a dual receptor system analogous to that of the fibroblast growth factors and many other protein ligands that regulate cell function in development, homeostasis and disease. This transpires to be the case.  Others in the glycosaminoglycan community were active, exploring structure-function and how binding to heparan sulfate is a prerequisite for the Spike protein to load onto ACE-2. Thus, in this respect Spike looks like a classic endogenous heparan sulfate-dependent ligand, requiring a ternary complex of ligand, heparan sulfate co-receptor and transmembrane protein receptor.

Enter stage left neuropilin-1 (NRP-1). In our excitement we had forgotten about this. The Spike protein binds NRP-1, e.g., here. It likely that this is at least one of the mechanisms whereby it accesses the brain

e.g., here and here), through binding NRP-1 on olfactory neurones or via the blood-brain barrier (NRP1 remember is also important in controlling angiogenesis). The interaction with NRP-1 is predictable. NRP-1 binds heparin and is a heparin binding binding protein. That is its acidic domains are reasonably heparin mimetic and enable it to bind to some, but by no means all, heparin-binding proteins. To confound matters, NRP-1 is a facultative proteoglycan, so can carry a heparan sulfate (or chondroitin sulfate) chain. It is worth noting the anatomical symmetry of the nervous system and the vasculature extends to the molecular level, with NRP-1 being a prime example of the latter. What the is glycanation status of NRP-1 on the olfactory neurons? Nobody knows. An interesting aside here is the link between 3-O sulfation of heparan sulfate and NRP-1.

Frustrations

There are many, many loose ends

The RBD and the Spike protein are very difficult proteins to work with. Regardless of the source of the protein, it loses heparin-binding ability very easily, which correlates with a conformational change in the protein, detectable by circular dichroism – and this quite a long time before any decrease in ACE2 binding can be observed. There is also something unusual in the interaction of the RBD with heparin in vitro. You need SDS to dissociate the RBD (here and here). I have seen this some years ago with thrombospondin (TSH), where we had to use urea to dissociate bound thrombospondin. This was never published, as the data were consequently rather messy. My explanation was that the binding reaction was a two step process

TSH + HS = TSH:HS > TSH*:HS 

Where TSH* is a conformation induced by the initial reversible binding event, which results in  complex that cannot dissociate. Something similar may be happening with Spike, and which would mean that heparanase may play an important role in mediating the loading of SARS-CoV-2 onto ACE2. At least one heparanase inhibitor is a potent in vitro inhibitor of SARS-CoV-2 infection and it may be that the inhibitory effects of a number of sulfated sugars are due in part to inhibiting heparanase.

Therapy

First to vent some frustration. The world spent millions on clinical trials based on fraudulent data (hydroxychloroquine,  ivermectin) while people were dying, and nothing on trials targetting the heparan sulfate-dependent mechanism of SARS-CoV-2. This despite the fact that (1) coagulopathy is treatable with heparins and (2) there are heparan sulfate inspired products that are excellent stimulators of wound repair in the context of chronic inflammation, e.g., lower limb diabetic ulcers from OTR3. A clinical trial of heparin in non-SARS-CoV-2 ARDS looked very promising (sadly behind a paywall). We now have a first study in SARS-CoV-2 and it is rather disappointing – no major effect. 

Why might that be? The most likely explanation is that heparin is not the right compound. Though widely used as an anticoagulant, it is a very specialised fraction of heparan sulfate, produced by the mast cell. Compared to heparan sulfate, heparin is very short, highly sulfated and lacks the extensive domain structure of heparan sulfate. The much longer heparan sulfate, with its N-acetyl and transition domains separating the sulfated domains has far greater reach and is able to bend quite sharply – this is seen with VEGF, which heparin binds rather poorly, since it has trouble engaging both binding sites on the VEGF dimer. The ability of HS to bridge several proteins is likely important in its functions (remember, in tissues and on cells there is only heparan sulfate, no heparin). These functions relate to binding over 800 extracellular proteins that regulate cell communication. So rather than heparin, a heparanase resistant mimetic of heparan sulfate like the OTR3 compounds may be the molecules of choice. There is as yet only anecdotal off label case reports, but these all suggest such compounds may be very effective both against SARS-CoV-2 and in reversing the molecular pathology of LongCovid, which include, but is not restricted to microclots.

Thanks to Byline Times for the tip!

The sale of such information is part of the Grand Sale of the NHS, which has been taking place since Thatcher came to power in 1978. A quick check of the effectiveness of health systems around the world will show that the private sector is not able to deliver adequate healthcare. Indeed the profit motive and the Hippocratic Oath are hardly compatible.

With Project SHAPE progressing in the Faculty of Health and Life Sciences at the University of Liverpool, we have now moved onto the compulsory redundancy stage. As a senior member of staff who went back to the trenches after ten years in management, I have been contacted informally by a number of staff who have been sent a notice that they are at risk of redundancy. So I used my experience in management and my knowledge of the University to figure what may be important for retention in the Faculty of Health and Life Sciences at the University of Liverpool and, perhaps more important, what may kill your career and result in a P45.

1. Publish work that is well cited, regardless of any ethical or quality issues.

2. Obtain grants as a PI that are registered on the university’s IRIS system as external funding.

3. Taking on an administrative role. The original list was 77 strong, 30 were removed before letters were sent out to individual staff, because they had important administrative roles.

What is not important to your career and may put you at risk of redundancy, because these factors are not considered in redundancy.

1. Overseas PhD students that pay full fees. This, despite the fact that Liverpool has a lower PhD/staff ratio than comparator universities and increasing PhD student numbers has long been a priority. However, these funds do not count as ‘grant income’.

2. UK sourced awards for PhD students, over and above the DTP programmes. As for overseas students, such training awards often do not count.

3. Three  or more times the number of papers required for REF and that meet internal standards of REF 3* and 4*. Staff with this number of quality papers are, of course, the dream for REF panels, as they can pick and mix to suit narrative, etc., but this will not save your job.

4. Co-investigator status on a grant. This is despite the averred  ambition to increase cross disciplinary work, which is one of the publicised drivers behind Project Shape and the obvious fact that cross-disciplinary research requires input from different disciplines, but only one person can be PI (usually the person that fits the remit of the funder best).

5. Leading a teaching module. With ~75% of income from undergraduate teaching, this is apparently not a task that is important and certainly not as important as an admin role.

6. Maintaining student/staff ratios such that a degree remains professionally accredited and so attractive to prospective undergraduates.

7. Running a major Facility and obtaining large equine grants that ensure it is state-of-the-art. Facilities that are 100% ‘open access’, that is open (with full training provided) to intramural and extramural users, the latter including industry is core to a strong research enterprise and collaboration with industry.

A number of points are worth noting.

(i) The only academic staff on Research and Teaching contracts who pay their way by research and don’t have to teach (but they usually do) are those who are externally funded.

(ii) The Faculty of Medicine of the past was always in notional debt to the Centre. That is, its contribution to the Centre per staff FTE was below that of the other Faculties. I suspect this was a driver of the merging of Faculties in 2010, as the publicised reasons (more streamlined, fewer layers between staff and the Vice-Chancellor) did not bear a nanosecond of scrutiny (the number of layers was Staff-Department Head-Dean-Pro VC-VC = 5, now it is Staff-Department Head-Dean (or Head of School)-executive Pro VC-VC = 5). 

So, by bolting on two units from the Faculty of Science, and the Faculties of Veterinary Medicine and Dentistry, it was hoped to make good the deficit in the Faculty of Medicine contribution/staff FTE. My suspicion is that no one bothered to do the calculations and there is still a deficit. 

(iii) It is possible to improve the research output of a unit, small or large. I was involved in this over three decades in Biochemistry and then in the wider context of Biological Sciences and what we have today is unrecognisable.  How the present re-organisation will strengthen research has yet to be explained: what weaknesses are addressed and what will be the evidence that they have been addressed?

This augurs badly for the long-term strength of the Faculty. There will be a strong buyers’ market for staff post REF. Moreover, BREXIT has not only strangled the supply of staff from the rest of Europe, but existing non-British European staff (especially the young, the leaders of the future) will continue to gradually leave. The result is filling posts and recruitment are going to be more competitive than ever, yet the above sends a clear signal to staff to seize external job offers without hesitation, will make people hesitant to apply for jobs in Liverpool and competition form other UK universities will be fierce.

1.  No enforced quarantine for international travellers, starting in March 2020.

2. Allowing both Liverpool away and home matches in March.

3. Allowing Dido Harding to go ahead with Cheltenham races.

4. Locking down too late in March 2020 and no control over interactional travel during 1^st lockdown.

5. Not implementing a full mask policy by March 2020, when aerosols were known to be main rout of transmission.

6. No measures at transport hubs such as airports, railway stations, major bus terminals, e.g., thermal imaging cameras: not perfect, but will stop symptomatic travellers.

7. Failing to beef up NHS testing and instead spaffing cash on private sector testing.

8. After 1^st lockdown, continuing to allow international travel, rather than focussing on supressing virus: Scotland was 2 weeks, England ~1 months away in July 2020.

9. Late lockdown in November 2020.

10. Early release of lockdown in December = early Christmas for virus.

11. Continued absence of proper border controls for travellers and one month late in putting India on red list.

12. Reversal of school mask policy, despite deep understanding of aerosol transmission, and no implementation of rules on air exchange determining number of people in a room.